Most autoimmune diseases are found with higher frequency in women. In fact, almost 80 percent of patients with autoimmune disease are women. This suggests that the autoimmune phenotype is related to gender-associated immunologic changes that could stem from sex hormone effects, genetic factors and/or neuroendocrine effects. Multiple sclerosis (MS) is a central nervous system (CNS) demyelinating disease of unknown etiology that is believed to be mediated by autoreactive T lymphocytes directed against CNS proteins including myelin basic protein (MBP) and proteolipid protein (PLP). MS is found 2 to 3 times more often in women than in men. Based on numerous similarities between MS and the animal model for MS, experimental autoimmune encephalomyelitis (EAE), it has been postulated that Th1-like T cells are involved in the pathogenesis of MS. What has also been learned from EAE is that production of pro-inflammatory cytokines such as IFNgamma and TNFalpha/beta are considered to be crucial for the initiation and amplification of inflammatory brain lesions and possibly also for direct myelin damage. In previous studies, we have shown a significant difference in the IFNgamma response to PLP peptides between MS patients and controls. In the current preliminary data, we present evidence to support gender differences in the cytokine response to PLP. Thus, we hypothesize that the increased incidence of MS in females is in part due to a gender-related increase in Th1 cytokines in females as compared to males. Because upregulation of inflammatory cytokines generally requires expression of costimulatory molecules, some of which have been implicated in MS attacks, we also hypothesize that costimulatory molecules may shown differential gender expression. We propose to examine three inter-related immune effects that may underlie the higher incidence of Ms in females: (I) increased inflammatory (Th1) cytokine versus regulatory (Th2) cytokine secretion in females compared to males stimulated by proteins that are thought to be targets in MS; (II) the role of the cytokine IL-12 and costimulatory molecules in promoting gender differences; (III) the effect of sex hormones on cytokine secretion and on costimulation. Cytokines will be measured both at the single cell level using the n assay and in cell supernatants using ELISA. Cell surface molecules will be measured by flow cytometry. Ultimately, the goal of these studies is to improve current therapy for MS patients and allow development of new therapies that capitalize on the different immunological responses in women versus men.